The long range goal of the NCDDG/AIDS is to develop drugs for the prevention and treatment of acquired immune deficiency syndrome (AIDS). Program 2 will define the low resolution structure of the envelope protein of the virus responsible for this disease. The specific aims are threefold. The first aim is to identify any structural domains of the protein which can be prepared by partial proteolytic cleavage and which retain native folded structure. The second aim is to determine whether the protein's cysteines exist as disulfides or as free sulfhydryl groups. If disulfides occur, the specific pairs of cysteines comprising the disulfides will be determined. The third goal is to identify the buried or exposed nature of different regions of the sequence. This information will assist in identifying exposed portions of the sequence which may function as peptide vaccines or targets for monoclonal antibodies. It will help define regions which interact with T4 lymphocytes and could be targets for drugs interfering with infection of lymphocytes. Data also will define regions which interact with viral matrix proteins called gag proteins and thereby could be targeted for drugs interfering with virus maturation. Finally, experiments will investigate whether naturally occurring proteolytic cleavage of envelope protein activates it for interaction with T4 cells. If so, drug inhibition of such cleavage might interfere with T4 infection. Envelop proteins produced in monkey cells will be treated with proteases, reagents modifying sulfhydryl groups and disulfides, and reagents which discriminate between tyrosines which are exposed on the surface or buried in the membrane lipid bilayer. Reagents and the envelope protein itself may incorporate radioactive labels to facilitate analysis of small amounts of material. Radiolabelled peptides of modified proteins will be separated by high pressure liquid chromatography and analyzed by a gas phase microsequencer to determine the position of modifications in the protein's amino acid sequence.